Compounds as cannabinoid receptor ligands

1. A compound according to formula (I), or a pharmaceutically acceptable salt thereof

wherein

X 4 is O, S, S(O), S(O) 2 , or N(R bx ); wherein R bX is hydrogen, alkyl, haloalkyl, alkoxyalkyl, —C(O)O(alkyl), monocyclic cycloalkyl, —(CR 1c R 1d ) q3 -(monocyclic cycloalkyl), or haloalkoxyalkyl; and

A 1 is —N(R b )C(O)R a , —N(R b )C(O)OR d , —N(R b )C(O)N(R b )(R c ), —N(R b )(R c ), or —N═C(R p )(R q ); or

X 4 and A 1 together is N═N(R cx );

each occurrence of R a and R c , are each independently hydrogen, alkyl, haloalkyl, —(CR 1a R 1b ) q3 -A 3 , G 1d , or —(CR 1a R 1b ) q3 -G 1d ;

R b , at each occurrence, is each independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, monocyclic cycloalkyl, —(CR 1c R 1d ) q3 -(monocyclic cycloalkyl), or haloalkoxyalkyl;

R d , at each occurrence, is each independently alkyl, haloalkyl, —(CR 1a R 1b ) q3 -A 3 , G 1d , or —(CR 1a R 1b ) q3 -G 1d ;

R cx is alkyl, haloalkyl, —(CR 1a R 1b ) q3 -A 3 , G 1d , or —(CR 1a R 1b ) q3 -G 1d ;

R p is hydrogen, alkyl, haloalkyl, —(CR 1a R 1b ) q3 -A 3 , —C(O)OR d , —C(O)R d , G 1d , or —(CR 1a R 1b ) q3 -G 1d ;

R q is hydrogen, alkyl, haloalkyl, —N(R b )(R c ), —(CR 1a R 1b ) q3 -A 3 , G 1d , or —(CR 1a R 1b ) q3 -G 1d ; or

R p and R q , together with the carbon atom to which they are attached, form a monocyclic 5-, 6-, 7-, or 8-membered ring, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo, alkyl, haloalkyl, and halogen;

A 3 is C(O)R h , —S(O) 2 R e , —C(O)N(R h ) 2 , —C(S)N(R h ) 2 , —S(O) 2 N(R h ) 2 , —C(═NOR h )R h , —N(R h )C(O)R h , —N(R h )C(O)OR e , —N(R h )S(O) 2 R e , —N(R h )C(O)N(R h ) 2 , —N(R h )S(O) 2 N(R h ) 2 , —CN, —OR h , or —N(R h ) 2 ;

A 5 represents formula (a),

G 1d , at each occurrence, is independently a monocyclic heterocycle, a monocyclic heteroaryl, a phenyl, a monocyclic cycloalkyl, or a monocyclic cycloalkenyl; wherein G 1d is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of —N(R h ) 2 , —CN, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, and OH;

R e , at each occurrence, is independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, monocyclic cycloalkyl, monocyclic heterocycle, or —(CR 1c R 1d ) q3 -(monocyclic cycloalkyl);

R h , at each occurrence, is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, monocyclic cycloalkyl, or —(CR 1c R 1d ) q3 -(monocyclic cycloalkyl);

R 21 is alkyl, alkenyl, alkynyl, haloalkyl, —(CR 2a R 2b ) q4 —OH, —(CR 2a R 2b ) q4 —O-alkyl, —(CR 2a R 2b ) q4 —O-haloalkyl, —(CR 2a R 2b ) q4 —O-G 2a , —(CR 2a R 2b ) q4 —O—(CR 2c R 2d ) q3 -G 2a , —(CR 2a R 2b ) q5 —C(O)—R a , —(CR 2a R 2b ) q5 —C(═N—OR f )R a , —(CR 2a R 2b ) q5 —SO 2 —R d , —(CR 2a R 2b ) q5 -G 2b , —(CR 2a R 2b ) q5 —C(O)N(R b )(R c ), or —(CR 2a R 2b ) q5 —CN;

R f , at each occurrence, is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —(CR 1c R 1d ) q3 —OR h , monocyclic heterocycle, monocyclic cycloalkyl, or —(CR 1c R 1d )-(monocyclic cycloalkyl);

each occurrence of G 2a is independently cycloalkyl, heterocycle, aryl, or heteroaryl;

G 2b is a monocyclic ring selected from the group consisting of cycloalkyl, cycloalkenyl, thienyl, phenyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, and heterocycle; wherein the heterocycle contains zero or one double bond, one or two oxygen, and zero or one nitrogen as ring atoms; two non-adjacent atoms of said heterocycle ring can be optionally linked by an alkenylene bridge of 2, 3, or 4 carbon atoms, or optionally linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms; each ring G 2b is optionally fused with a monocyclic ring selected from the group consisting of benzo, cycloalkyl, cycloalkenyl, heterocycle and heteroaryl;

each occurrence of G 2a and G 2b are each independently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of oxo, alkyl, halogen, —OH, alkoxy, haloalkoxy, and haloalkyl;

X 1 is S;

R 3 is G 3 , hydrogen, alkyl, alkenyl, alkynyl, —NO 2 , —CN, halogen, —OR h , —N(R h ) 2 , —C(O)R h , —C(O)O(R h ), haloalkyl, —(CR 3a R 3b ) q6 —OR h , —(CR 3a R 3b ) q6 —N(R h ) 2 , —(CR 3a R 3b ) q6 —C(O)R h , or —(CR 3a R 3b ) q6 —C(O)O(R h );

G 3 , at each occurrence, is independently cycloalkyl, cycloalkenyl, aryl, heterocycle, or heteroaryl, wherein each G 3 is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, halogen, C 1 -C 4 haloalkyl, ═N—CN, ═N—OR h , —CN, oxo, —OR h , —OC(O)R h , —OC(O)N(R h ) 2 , —S(O) 2 R e , —S(O) 2 N(R h ) 2 , —C(O)R h , —C(O)OR h , —C(O)N(R h ) 2 , —N(R h ) 2 , —N(R h )C(O)R h , —N(R h )S(O) 2 R e , —N(R h )C(O)O(R e ), and —N(R h )C(O)N(R h ) 2 ;

R 1a , at each occurrence, is independently hydrogen, halogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl;

R 1b , at each occurrence, is independently hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 haloalkyl, —OR h , —N(R h ) 2 , —N(R h )C(O)R h , —N(R h )C(O)OR e , or —N(R h )S(O) 2 R e ;

R 1c , R 1d , R 2a , R 2b , R 2c , R 2d , R 3a and R 3b , at each occurrence, are each independently hydrogen, halogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl;

R x at each occurrence, is each independently G 1d , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, halogen, C 1 -C 4 haloalkyl, NO 2 , —CN, —OR f , —OC(O)R f , —OC(O)N(R f ) 2 , —S(O) 2 R e , —S(O) 2 N(R f ) 2 , —C(O)R f , —C(O)OR f , —C(O)N(R f ) 2 , —N(R f ) 2 , —N(R f )C(O)R f , —N(R f )S(O) 2 R e , —N(R f )C(O)O(R e ), —N(R f )C(O)N(R f ) 2 , —(CR 1c R 1d ) q3 —OR f , —(CR 1c R 1d ) q3 —OC(O)R f , —(CR 1c R 1d ) q3 —OC(O)N(R f ) 2 , —(CR 1c R 1d ) q3 —S(O) 2 R e , —(CR 1c R 1d ) q3 —S(O) 2 N(R f ) 2 , —(CR 1c R 1d ) q3 —C(O)R f , —(CR 1c R 1d ) q3 —C(O)OR f , —(CR 1c R 1d ) q3 —C(O)N(R f ) 2 , —(CR 1c R 1d ) q3 —N(R f ) 2 , —(CR 1c R 1d ) q3 —N(R f )C(O)R f , —(CR 1c R 1d ) q3 —N(R f )S(O) 2 R e , —(CR 1c R 1d ) q3 —N(R f )C(O)O(R e ), —(CR 1c R 1d ) q3 —N(R f )C(O)N(R f ) 2 , or —(CR 1c R 1d ) q3 —CN;

q4, at each occurrence, is independently 2, 3, 4, or 5;

q3, at each occurrence, is 1, 2 or, 3;

q5 and q6, at each occurrence, are each independently 1, 2, 3, 4, 5, or 6;

z is 0, 1, 2, 3, or 4; and

the monocyclic cycloalkyl and the monocyclic heterocycle, as a substituent or as part of a substituent, of R bx , R b , R e , R f , and R h , are each independently unsubstituted are substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of oxo, C 1 -C 4 alkyl, halogen, OH, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and C 1 -C 4 haloalkyl;

with the proviso that when

X 4 is S(O) 2 , and

R 21 is alkyl, alkynyl, haloalkyl, —(CR 2a R 2b ) q4 —O-alkyl, —(CR 2a R 2b ) q4 —OH, —(CR 2a R 2b ) q5 —C(O)-(monocyclic heterocycle), —(CR 2a R 2b ) q5 —C(O)N(R b )(R c ), —(CR 2a R 2b ) q5 —CN, or —(CR 2a R 2b ) q5 -G 2b wherein G 2b is monocyclic cycloalkyl or phenyl;

then A 1 is not N(H) 2 , N(H)(alkyl), or N(alkyl) 2 .

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein

A 1 is —N(R b )(R c ).

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein

X 4 is O or N(R bx ); and

R bx is hydrogen, alkyl, or —C(O)O(alkyl).

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R 21 is alkyl, alkenyl, alkynyl, haloalkyl, —(CR 2a R 2b ) q4 —O-alkyl, —(CR 2a R 2b ) q4 —O-haloalkyl, —(CR 2a R 2b ) q5 -G 2b , or —(CR 2a R 2b ) q5 —CN.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein

A 1 is —N(R b )(R c ).

6. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein

A 1 is —N(R b )C(O)R a , —N(R b )C(O)OR d , —N(R b )C(O)N(R b )(R c ), or —N═C(R p )(R q ).

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein

X 4 and A 1 together is N═N(R cx ); and

R 21 is alkyl, alkenyl, alkynyl, haloalkyl, —(CR 2a R 2b ) q4 —O-alkyl, —(CR 2a R 2b ) q4 —O-haloalkyl, —(CR 2a R 2b ) q5 -G 2b , or —(CR 2a R 2b ) q5 —CN.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of

2-[(tert-butylamino)oxy]-N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-2-{(2Z)-2-[(6-methylpyridin-2-yl)methylene]hydrazino}-5-(trifluoromethyl)benzamide;

tert-butyl 2-({[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]amino}carbonyl)-4-(trifluoromethyl)phenoxycarbamate;

N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-2-[2-(4-fluorobenzoyl)hydrazino]-5-(trifluoromethyl)benzamide;

N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-2-[(isopropylamino)oxy]-5-(trifluoromethyl)benzamide;

2-[(tert-butylamino)oxy]-N-[(2Z)-3-butyl-5-(1-methylcyclopropyl)-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

2-[(tert-butylamino)oxy]-N-[(2Z)-5-tert-butyl-3-(tetrahydro-2H-pyran-2-ylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-2-[(E)-tert-butyldiazenyl]-5-(trifluoromethyl)benzamide;

N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)-2-({[(1E)-1,2,2-trimethylpropylidene]amino}oxy)benzamide;

2-[(tert-butylamino)oxy]-N-[(2Z)-5-tert-butyl-3-(3-cyanopropyl)-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

2-[(tert-butylamino)oxy]-N-[(2Z)-5-tert-butyl-3-isobutyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

2-[(tert-butylamino)oxy]-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

2-[(acetylamino)oxy]-N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

2-[(tert-butylamino)oxy]-N-[(2Z)-5-tert-butyl-3-(2-methoxyethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

2-[(tert-butylamino)oxy]-N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-chlorobenzamide;

2-[(tert-butylamino)oxy]-N-[(2Z)-5-tert-butyl-3-(cyclopropylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

2-[(tert-butylamino)oxy]-N-[(2Z)-5-tert-butyl-3-(4,4,4-trifluorobutyl)-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

2-[(tert-butylamino)oxy]-N-[(2Z)-5-tert-butyl-3-(cyclobutylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

2-({[1-amino-2,2-dimethylpropylidene]amino}oxy)-N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-2-{[(1-methylethylidene)amino]oxy}-5-(trifluoromethyl)benzamide;

N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-2-{[(2,2-dimethylpropanoyl)amino]oxy}-5-(trifluoromethyl)benzamide;

2-[(tert-butylamino)oxy]-N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-4-(trifluoromethyl)benzamide;

N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-2-[(dimethylamino)oxy]-5-(trifluoromethyl)benzamide;

N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)-2-({[2,2,2-trifluoro-1-methylethylidene]amino}oxy)benzamide;

N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-2-(2-tert-butylhydrazino)-5-(trifluoromethyl)benzamide;

2-[(tert-butylamino)oxy]-N-[(2Z)-5-tert-butyl-3-(4-fluorobutyl)-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

2-({[1-amino-2-methylpropylidene]amino}oxy)-N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

ethyl amino {[2-({[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]amino}carbonyl)-4-(trifluoromethyl)phenoxy]imino}acetate;

2-[(tert-butylamino)oxy]-N-[(2Z)-5-tert-butyl-3-(oxetan-2-ylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-2-({[(1E)-1-methyl-2-oxopropylidene]amino}oxy)-5-(trifluoromethyl)benzamide;

tert-butyl 2-[2-({[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]amino}carbonyl)-4-(trifluoromethyl)phenyl]hydrazinecarboxylate;

2-({[amino(4-fluorophenyl)methylene]amino}oxy)-N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-2-(2-pyridin-2-ylhydrazino)-5-(trifluoromethyl)benzamide;

tert-butyl 2-[2-({[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]amino}carbonyl)-4-(trifluoromethyl)phenyl]-1,2-dimethylhydrazinecarboxylate;

2-({[1-amino ethylidene]amino}oxy)-N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

2-({[1-aminopropylidene]amino}oxy)-N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-2-[2-(1-methylethylidene)hydrazino]-5-(trifluoromethyl)benzamide;

2-({[amino(cyclopropyl)methylene]amino}oxy)-N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

2-{[azepan-2-ylideneamino]oxy}-N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-2-[(cyclopentylideneamino)oxy]-5-(trifluoromethyl)benzamide;

N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-2-(2-isonicotinoylhydrazino)-5-(trifluoromethyl)benzamide;

methyl 2-[2-({[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]amino}carbonyl)-4-(trifluoromethyl)phenyl]hydrazinecarboxylate;

N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-2-[2-(2,2-dimethylpropanoyl)hydrazino]-5-(trifluoromethyl)benzamide;

2-({[amino(pyridin-2-yl)methylene]amino}oxy)-N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-2-[2-(pyridin-3-ylcarbonyl)hydrazino]-5-(trifluoromethyl)benzamide;

2-[2-({[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]amino}carbonyl)-4-(trifluoromethyl)phenyl]hydrazinecarboxamide;

2-(2-benzylhydrazino)-N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

2-({[amino(pyridin-4-yl)methylene]amino}oxy)-N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

2-({[amino(pyridin-3-yl)methylene]amino}oxy)-N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

tert-butyl (2E)-1-[2-({[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]amino}carbonyl)-4-(trifluoromethyl)phenyl]-2-[(6-methylpyridin-2-yl)methylene]hydrazinecarboxylate; and

N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-2-{(2E)-2-[(6-methylpyridin-2-yl)methylene]hydrazino}-5-(trifluoromethyl)benzamide.

9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.